Midazolam activates caspase, MAPKs and endoplasmic reticulum stress pathways, and inhibits cell cycle and akt pathway, to induce apoptosis in TM3 mouse Leydig progenitor cells

Fu Chi Kang, Shu Chun Wang, Ming Min Chang, Bo Syong Pan, Kar Lok Wong, Ka Shun Cheng, Edmund Cheung So, Bu Miin Huang

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Background: Midazolam (MDZ) has powerful hypnosis, amnesia, anti-anxiety and anticonvulsant effects. Studies have shown that prenatally developmental toxicity of diazepam can be observed in many organs/tissues. However, it remains elusive in male reproductive system. Materials and methods: TM3 mouse Leydig progenitor cell line was used to determine whether MDZ has any unfavorable effects. Results: Midazolam significantly decreased cell viability in dose- and time-dependent manners in TM3 cells. In flow cytometry analysis, midazolam significantly increased subG1 phase cell numbers, and annexin V/PI double staining assay further confirmed that MDZ induced apoptosis in TM3 cells. Moreover, MDZ significantly induced the expression of caspase-8 and -3 proteins and the phosphorylation of JNK, ERK1/2 and p38. Besides, MDZ didn’t activate Akt pathway in TM3 cells. Furthermore, the expressions of p-EIF2α, ATF4, ATF3 and CHOP were induced by midazolam, suggesting that midazolam could induce apoptosis through endoplasmic reticulum (ER) stress in TM3 cells. Additionally, the expressions of cyclin A, cyclin B and CDK1 were inhibited by midazolam through the regulation of p53 in TM3 cells, indicating that midazolam could regulate cell cycle to induce apoptosis. Conclusion: Midazolam could activate caspase, MAPKs and ER stress pathways and impede Akt pathway and cell cycle to induce apoptosis in TM3 mouse Leydig progenitor cells.

Original languageEnglish
Pages (from-to)1475-1490
Number of pages16
JournalOncoTargets and Therapy
Volume11
DOIs
Publication statusPublished - 2018 Mar 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pharmacology (medical)

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